Tags

Type your tag names separated by a space and hit enter

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.
N Engl J Med. 2020 06 11; 382(24):2289-2301.NEJM

Abstract

BACKGROUND

Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.

METHODS

In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.

RESULTS

A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.

CONCLUSIONS

Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

Authors+Show Affiliations

From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).No affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32521132

Citation

Balwani, Manisha, et al. "Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria." The New England Journal of Medicine, vol. 382, no. 24, 2020, pp. 2289-2301.
Balwani M, Sardh E, Ventura P, et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020;382(24):2289-2301.
Balwani, M., Sardh, E., Ventura, P., Peiró, P. A., Rees, D. C., Stölzel, U., Bissell, D. M., Bonkovsky, H. L., Windyga, J., Anderson, K. E., Parker, C., Silver, S. M., Keel, S. B., Wang, J. D., Stein, P. E., Harper, P., Vassiliou, D., Wang, B., Phillips, J., ... Gouya, L. (2020). Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. The New England Journal of Medicine, 382(24), 2289-2301. https://doi.org/10.1056/NEJMoa1913147
Balwani M, et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 06 11;382(24):2289-2301. PubMed PMID: 32521132.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. AU - Balwani,Manisha, AU - Sardh,Eliane, AU - Ventura,Paolo, AU - Peiró,Paula Aguilera, AU - Rees,David C, AU - Stölzel,Ulrich, AU - Bissell,D Montgomery, AU - Bonkovsky,Herbert L, AU - Windyga,Jerzy, AU - Anderson,Karl E, AU - Parker,Charles, AU - Silver,Samuel M, AU - Keel,Siobán B, AU - Wang,Jiaan-Der, AU - Stein,Penelope E, AU - Harper,Pauline, AU - Vassiliou,Daphne, AU - Wang,Bruce, AU - Phillips,John, AU - Ivanova,Aneta, AU - Langendonk,Janneke G, AU - Kauppinen,Raili, AU - Minder,Elisabeth, AU - Horie,Yutaka, AU - Penz,Craig, AU - Chen,Jihong, AU - Liu,Shangbin, AU - Ko,John J, AU - Sweetser,Marianne T, AU - Garg,Pushkal, AU - Vaishnaw,Akshay, AU - Kim,Jae B, AU - Simon,Amy R, AU - Gouya,Laurent, AU - ,, PY - 2020/6/11/entrez PY - 2020/6/11/pubmed PY - 2020/6/26/medline SP - 2289 EP - 2301 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 382 IS - 24 N2 - BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.). SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/32521132/Phase_3_Trial_of_RNAi_Therapeutic_Givosiran_for_Acute_Intermittent_Porphyria L2 - http://www.nejm.org/doi/full/10.1056/NEJMoa1913147?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -